Biotech poop save me

yuh

12 years, 4.54 billion

Research and development of new medicines takes over ____ from the identification of a drug candidate to its introduction and can cost up to _____

Artemisinin (antimalarial)

Artemisia annua

Bakuchiol (anticancer)

psoralea corylifolia

Piperine (Nor A inhibitor)

Piper nigrum

Resveratrol (Anti-Alzheimer)

Veratrum grandiflorum

Curcumin (anti-inflammitory)

Curcuma longa

Lycopene (Antioxidant)

Solanum lycopersicum

Endo’s hypothesis

fungi like molds and mushrooms would produce antibiotics that inhibited HGM-CoA reductase. Inhibition of HMG-CoA reductase would thus be lethal to these microbes

MOA of Endo’s hypothesis (compactin)

lower cholesterol levels in the blood. Statins inhibit the production of cholesterol in the liver, helping to reduce the risk of cardiovascular diseases

Compactin

-isolated from a culture broth of blue-green mold, Penicillium cinitrum Pen-51, which was isolated from a rice sample collected at a grain shop in Kyoto.

-Inpsired other pharmaceutical companies to identify other statins

5.9%

Statins market forecasted to grow at a compound annual growth rate of 5.9%

Forodesine MOA

increased level of dGTP inhibits the ribonucleotide reductase enzymatic activity, resulting in reduction of 2-deoxycytidine triphosphate (dCTP) and 2-deoxythymidine triphosphate. Therefore, an increase in dGTP will disrupt the deoxynucleptide pool, which inhibits DNA synthesis and eventually leads to apoptosis

forodesine Molecular Target

Purine nucleoside phosphorylase (PNP)

3 benefits of AI

• Time and Cost savings

  • Time and cost savings for drug discovery when using AI could reach between 25-50%

• Increased probability of success

  • AI and ML could help teams select optimal therapeutics or generate hypotheses for experiments that had otherwise been missed

• The discovery of novel therapeutics

  • AI could discover nobel therapeutics that can tackle a wider array of biological/chemical space and offer the option to treat previously undruggable diseases

Roles of biotherapeutics

• gene editing

• mRNA
  monoclonal antibodies

• recombinant proteins

• cell therapies

Biologics (biotherapeutics)

therapeutic protein or nucleic acid preparations made by techniques involving recombinant DNA and encompass a range of products, each service unique therapeutic roles

understanding the genetic disease/disorder

in a normal/mutant heterozygote, if the single normal allele can provide adequate functional protein, the mutant allele is dominant

gene repair, gene supplementation, gene silencing

3 gene therapy strategies

3 ex vivo gene therapy strategies

• tissue extraction

• cells modified and amplified

• cell transplantation

In vivo (systematic or local administration) gene therapy strategies

Non-Viral Vectors:

• Cationic polymer

• Lipid nanoparticles

Viral Vectors:

• AAV

• Adenovirus

• Lentivirus

Ashanti De Silva

First patient to be treated with gene therapy based on adenovirus as a vector (for ADA)

Jesse Gelsinger

Major setback occurred in 1999 when the first death was reported _____ had a genetic disease called ornithine transcaramylase deficiency which prevents the body from breaking down ammonia, a metabolic waste product. The excessive buildup of ammonia often causes death soon after birth. He lived on a strict non-protein diet and controlled his OTC fairly well.

-He thought volunteering could help newborns affiliated with OTC A modified version of the virus that causes the common cold carrying a normal OTC gene was injected into his liver.

-He died from a massive immune response-mediated organ failure after receiving a high dose of an adenoviral gene therapy.

-Years of regulatory caution followed this affair

uniQure, EMA, Glybera

In 2012, ____ secured ___ approval for its lipoprotein lipase LPLD therapy _____.

In 2017, missed approval in the United States and _____ was terminated. Cost: 1M per injection

Mechanism of action for Glybera

Glybera contains the human LPL gene variant LPL S447X in an adeno-associated virus serotype 1 (AAV1) vector intended to target the muscle. Glybera is injected as a one-time series into the muscle of the lower extremities where it is taken up by myocytes. The elements of the vector were chosen such that expression of the LPL S447X gene is promoted, by co-opting the expression machinery of the cell and myocytes produce the protein product of the transgene LPL S447X without the vector being able to produce itself"

Gene therapy with adenovirus

-Repeated use of the adenoviral vector induces strong immunogenicity of the vector itself, which often induces the body to produce neutralizing (NAs) antibodies agaisnt the adenovirus (AdV)

-NAs against multiple serotypes of AdV are commonly found in the population, resulting in rapid clearance of the adenoviral vector by the host immune system, affecting transduction efficiency and duration of the exogenous gene

TALENs

Transcription activator-like effector nucleases

CRISPR

Clustered regularly interspaced short palindromic repeats associated protein

Transfusion-dependent B-thalassemia (TDT) and sickle cell disease (SCD)

-Are the most common monogenic diseases worldwide, with an annual diagnosis in approx. 60,000 patients with TDT and 300,000 patients with SCD.
-Both diseases are caused by mutations in the hemoglobin B subunit (HBB):

• Mutations in HBB that cause TDT4 result in B+ or absent B0 B-globin synthesis and an imbalance between the a-like and B-like globin chains of hemoglobin, which causes ineffective erythropoisis.

• Sickle hemoglobin is the result of a point mutation in HBB that replaces glutamic acid with valine at amino acid position. Polymerization of deoxygenated sickle hemoglobin causes eythrocyte deformation, hemolysis, anemia, painful vaso-occusive episodes, irreversible end-organ damage, and a reduces life expectancy

Pros and cons of LNPS

Pros:

• High homogeneity

• Penetrations of BBB and blood vessels

• efficeint cargo loading

• Scalaiblity

Cons

• Low biolvompatibility

• Immunulogic concerns

• Cellular toxicity

• Limtied tropism

• Rapid clearing after systemic administration

Pros and cons for Extracellular vesicles

Pros

• High biocompatibility

• Low immunogenicity

• Low tumerigenesis Tropism

• Penetration of BBB and blood vessels

• Endogenous mechanisms for delivery

Cons

• Low homogeneity

• Inefficient cargo loading

• Limited scalability

• Lack of manufacturing criteria

Pros and cons of cells

Pros

• high biocompatibility

• Long in vivo retention

• Large and efficient cargo loading

• Scalability

Cons

• Potenial tumorigenesis

• HLA matching

Pros and cons of biomimeitcs

Pros

• High biocompatibilitu

• Low immunogenicity

• Low tumorigenesis

• Long in vivo retention

• Penetration of BBB and blood vessels

• Efficient cargo loading

Cons

• Unclear biological mechanism

• Lack of manufacturing criteria

1990s

first mRNA flu vaccine was tested in mice

2013

the first mRNA vaccines for rabies were tested in humans

primary challenge of mRNA vaccines

ensuring that the mRNA would be taken up by the body and not degrade quickly

Katalin Kariko and Drew Weissman

2023 nobel prize for their discoveries to modify the RNA (covid vaccine?)

Emma Wead

received engineered HIV virus to attack cancer cells in the blood

Asbestos

The main risk factor for mesothelioma

Prostate

Most common cancer in men

Most common cancer in women

Breast

1 in 3

Lifetime probability of developing cancer

lung and bronchus

Deadliest cancer (by numbers)

Pancreatic cancer

Deadliest cancer (by survival rate)

Avian Leukosis virus

benign growths, usually in lymphoid tissue

Rous sarcoma vrius

connective tissue malignant cancer that killed host

RSV has extra gene called “SRC”

Evidence that genetic variation is a major ffactor in cacner development

No-viral causes of cancer

• Cells can be oncogenically tranformed by chemicals. radiation, strong uv light

• Chemical carcinogens, radiation = DNA damage = mutations

Oncogene, Tumor suppresor

Two types of mutations are necessary for cancer development

Metastatic

Cancer cells that leave their site of origin

Therapeutics for cancer treatment

• poisons of metabolic processes

• small molecule inhibitors of enzyme function (kinase inhibitors)

• monoclonal antibodies that target tumor antigens

• monoclonal antibdies that block inhibition of immune killing cancer cells

• engineering of immune cells specific for type of tumer (CAR-T)

upregulation of the abl oncogene

cause of chronic myelogenous leukemia

Omacetaxine

Second gen kinase inhibitor, must be taken daily for the rest of person’s life

Tumor-infiltrating lymphocytes

uses small number of body’s T cells that see a tumor as a threat and reproduces them in lab (amtagvi)

gyclogojugate vaccines

Bacterial polysaccharides are linked to suitable carrier to elicit a longer lasting immune effect

Pros and cons of GV

Pros

• high yield

• no genetic engineering of bacteria

Consd

• use of pathogenic bacteria

• multiple purification and chemical treatment steps

• random chemical cross-linking

• previously too expensive to manufacture for use in livestock